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Chimeric antigen receptor and use thereof

A chimeric antigen receptor, dectin-1 technology, applied in the direction of antibody medical components, antibody mimics/scaffolds, carriers, etc., can solve the problem of lack of tumor-specific antigens, CAR-T cell exhaustion, damage to CAR-T cells Tumor effectiveness and other issues to achieve the effect of reducing exhaustion and increasing cell expansion

Active Publication Date: 2021-07-23
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Such as lack of appropriate tumor-specific antigens, tumor microenvironmental suppression, and insufficient CAR-T cell localization and persistence
In addition, continuous antigen exposure can lead to CAR-T cell exhaustion, which in turn impairs the effectiveness of CAR-T cells against tumors

Method used

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  • Chimeric antigen receptor and use thereof
  • Chimeric antigen receptor and use thereof
  • Chimeric antigen receptor and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] 1. Materials and methods

[0052] Cell lines: All cell lines were derived from ATCC. Combine K562 cells (myeloid leukemia) and NALM6 cells (lymphocytic leukemia) in RPMI-1640 with heat-inactivated 10% fetal bovine serum (FBS) (PAN, Germany.Cat: ST30-3302), penicillin (100 U / mL) (Gibco, Thermo Fisher, Waltham, MA. Cat: SV30010) and streptomycin (100ug / mL) (Gibco, Thermo Fisher, Waltham, MA. Cat: SV30010) were cultured together. Human cancer cell lines SK-OV-3 (ovarian cystadenocarcinoma) and MDA-MB-468 (breast cancer) were treated with heat-inactivated 10% FBS, penicillin (100U / mL) and streptomycin (100ug / mL) cultured in DMEM. SK-OV-3 was also engineered to express luciferase.

[0053] 2. Construction of plasmid encoding CAR

[0054] Anti-CD19 or anti-HER2 CARs included single-chain variable fragments (scFv) specific for CD19 (clone FMC63) or HER2 (clone 4D5). The scFv is followed by the human CD8α hinge region, followed by the human CD8α transmembrane domain (TM),...

Embodiment 2

[0082] 1. Novel CAR structure with Dectin-1 costimulatory domain

[0083] In the present invention, a novel second-generation CAR construct ( Figure 1A ). Two additional CAR constructs were generated using parts of the most popular second-generation CAR construct (human CD8αTM with 4-1BB and CD3δ ICDs). All constructed CARs were expressed on the surface of T cells ( Figure 1B ). Regarding CARs against HER2, the expression rate of hH8-BBz(4-1BB) CAR was 49.61%, and the expression rate of hHD-Dz(Dectin-1) CAR was 46.17%. Regarding the CARs against CD19, the expression rate of h198-BBz (4-1BB) CAR was 92.95%, and the expression rate of h19D-Dz (Dectin-1) CAR was 95.07%. Although the expression of anti-HER2 CARs was lower than that of anti-CD19 CARs, there was no significant difference in their expression levels among anti-HER2 or anti-CD19 CARs containing the same co-stimulatory signaling domain.

[0084] 2. Effect of Dectin-1 co-stimulation on the effector function of nov...

Embodiment 3

[0098] This embodiment also provides a co-stimulatory signaling domain of a chimeric antigen receptor, the co-stimulatory signaling domain comprising the intracellular region of RD-1.

[0099] Further, the co-stimulatory signal domain includes CD3δ.

[0100] Further, the intracellular region of RD-1 comprises the amino acid sequence of SEQ No.1 or an amino acid sequence not less than 90% identical to said SEQ No.1.

[0101] Further, the co-stimulatory signal domain also includes CD3, CD4, CD8, FcR, DAP10, DAP12, CD27, CD28, CD137, CD134, ICOS, OX40, CD30, CD40, PD-1, LFA-1, CD2, CD7 , LIGHI, NKG2C, B7-H3, ligands specifically binding to CD83, CDS, ICAM-1, GITR, BAFFR, HVEM (IGHTR), SLAMF7, NKp80 KLRE1, CD160, CD19, CD83, IL-2Rβ, IL-Rγ, IL-7Rα, ITGA4, VLA1, CD49α, ITGA4, IA4, CD49D, ITGA6, LA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11α, LFA-1, ITGAM, CDIIB, ITGAX, CD11c, ITGB1, CD29,ITGB2,CD18,LFA-1.ITGB7 TAFR2,TRANCE / RANKL,DNAM1(CD226),SLAMF4(CD244,2B4),CD84,CD96(Tact...

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Abstract

Provided is a chimeric antigen receptor, which comprises a co-stimulatory signal domain composed of an extracellular domain, a transmembrane domain and an intracellular domain, wherein the co-stimulatory signal domain comprises the full length or a fragment of the amino acids of encoded reverse dectin-1 and can treat multiple solid tumors and malignant hematological tumors.

Description

[0001] priority application [0002] This application claims the priority of the Chinese invention patent application [CN2020100907495] filed on February 13, 2020, titled "Co-stimulatory signaling domain of a chimeric antigen receptor and its application". The method is incorporated in its entirety. technical field [0003] The invention belongs to the field of biomedicine, and specifically relates to a chimeric antigen receptor and its application. Background technique [0004] Chimeric Antigen Receptor (CAR) T cell immunotherapy, as a very promising tumor treatment strategy, has undergone a series of evolutionary processes. The first-generation CAR-mediated T cell activation is accomplished through the tyrosine activation motif on CD3δ or FceRIg. However, the anti-tumor activity of the first-generation CAR-modified T cells is limited in vivo, because the reduction of T cell proliferation eventually leads to the apoptosis of T cells. The second-generation CAR adds a new ...

Claims

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Application Information

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IPC IPC(8): C07K19/00C12N15/867C12N5/10A61K39/00A61P35/00A61P35/02
CPCC07K16/2803C07K16/32C07K14/7051C07K14/7056C12N15/86C12N5/0636A61P35/00A61P35/02C07K2317/622C07K2319/03C07K2319/33C07K2319/74C12N2740/15043C12N2800/107C12N2510/00A61K2039/804A61K2039/812A61K2039/828A61K2039/892A61K2039/80A61K39/4631A61K2239/31A61K2239/38A61K2239/59A61K39/464412A61K39/4611A61K39/464406A61P37/02C12N2740/16043A61K2239/21A61K2239/22
Inventor 王玮魏于全
Owner SICHUAN UNIV
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